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Brexpiprazole hydrochloride new crystal form and preparation method thereof

A technology of ebiprazole hydrochloride and ebiprazole hydrochloride, which is applied in the field of new crystal forms of ebiprazole hydrochloride and its preparation, can solve problems such as time-consuming filtration steps, affecting the health of workers, and affecting production progress, so as to avoid Potential safety hazards and health risks, beneficial to large-scale production, and the effect of improving production efficiency

Pending Publication Date: 2020-07-24
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the inventors of the present application found in the process of producing ebiprazole that the ebiprazole hydrochloride prepared by the methods disclosed in the above two patents had a smaller crystal particle size, with a D90 between 5-25 μm, and the subsequent filtration steps took too long , seriously affecting the production schedule
Moreover, the high-temperature dropwise addition of acetic acid in the above-mentioned preparation method to dissolve the crude product of ebiprazole has serious potential safety hazards when applied to industrial production, prone to splashing and explosion accidents, and a large amount of volatilization of acetic acid at high temperature will seriously affect the health of workers. healthy

Method used

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  • Brexpiprazole hydrochloride new crystal form and preparation method thereof
  • Brexpiprazole hydrochloride new crystal form and preparation method thereof
  • Brexpiprazole hydrochloride new crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0036] Preparation Example 1: Preparation of Ebiprazole Crude Product

[0037] Adopt the method described in CN101155804A Example 1 to prepare the crude product of ebiprazole: 90g 7-(4-chlorobutoxy)-1H-quinolin-2-one, 100g 1-benzo[b]thiophen-4-yl- A mixture of piperazine hydrochloride, 140g potassium carbonate, 60g potassium iodide and 900mL DMF was stirred at 80°C for 2h, water was added to the reaction solution, and crystals were precipitated, separated by filtration and dried to obtain 130g of crude ebiprazole with a purity of 95.6%.

Embodiment 1

[0038] Embodiment 1: the impact of glacial acetic acid, ethanol addition on the dissolution of ebiprazole

[0039] When other conditions are the same, observe the influence of the adding amount of glacial acetic acid and 95% ethanol on the dissolution of ebiprazole.

[0040] Add 100 g of ebiprazole crude product prepared in Preparation Example 1 to the reaction flask, add 95% ethanol and glacial acetic acid as shown in Table 1 below, stir at room temperature, and observe the dissolution of ebiprazole.

[0041] When ebiprazole is completely dissolved, heat up to 45°C, add 1N HCl 310mL, stir for 30-60 minutes after the addition, cool down to 15°C, continue stirring and crystallizing for 30-60 minutes, filter the solid, wash with ethanol, and dry to obtain hydrochloric acid Ebiprazole, the results are shown in Table 1.

[0042] Table 1 The impact of glacial acetic acid and ethanol addition on the dissolution of ebiprazole

[0043]

[0044] The results show that when the amou...

Embodiment 2

[0047] Embodiment 2: the influence of crystallization temperature on the yield of ebiprazole hydrochloride

[0048]Add 100 g of crude ebiprazole (prepared in Preparation Example 1), 4 L of 95% ethanol and 300 mL of glacial acetic acid to the reaction flask, stir at room temperature to dissolve the ebiprazole, heat up to the crystallization temperature, add 230 mL of 1N HCl, and finish adding Afterwards, solids were precipitated, and the stirring was continued for 30-60 minutes, the temperature was lowered to 15° C., the stirring was continued, filtered, washed with ethanol, and dried to obtain ebiprazole hydrochloride.

[0049] The impact of table 2 crystallization temperature on ebiprazole hydrochloride crystal particle size and yield, purity

[0050]

[0051] The XRD pattern data of embodiment 2-3 see Figure 1-2 , the particle size distribution figure of embodiment 2-1~2-4 is as follows Figure 5-8 shown.

[0052] In the process of adjusting the crystallization temper...

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Abstract

The invention provides a brexpiprazole hydrochloride crystal form S and a preparation method thereof. The dosage of the mixed solvent of glacial acetic acid and ethanol relative to the brexpiprazole crude product is controlled, and the brexpiprazole crude product can be dissolved at normal temperature, thereby avoiding the potential safety hazard and health risk caused by dropwise adding acetic acid at high temperature. The novel brexpiprazole hydrochloride crystal form S with the particle size obviously larger than that of an existing crystal form is obtained by controlling the crystallization temperature, the filtering time can be shortened by 44%-60%, and the brexpiprazole hydrochloride crystal form S is very beneficial for reducing the time cost and improving the production efficiencyand is suitable for industrial production.

Description

technical field [0001] The patent relates to the preparation of medicines, in particular to a new crystal form of ebiprazole hydrochloride and a preparation method thereof. Background technique [0002] Ebiprazole (Brexpiprazole, structural formula shown in formula 1), the chemical name is 7-(4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1H -Quinolin-2-one, the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound developed by Otsuka Pharmaceutical Company, was approved for marketing in the United States on July 11, 2015. The trade name is Rexulti. This product can be used to treat adult schizophrenia, and can also be used as an adjuvant drug for the treatment of severe depression in adults. [0003] [0004] The prior art usually adopts the reaction of the crude product of ebiprazole (formula 1) and hydrochloric acid to generate ebiprazole hydrochloride (formula 2), and then removes the hydrochloric acid to obtain relatively pure e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12
CPCC07D409/12C07B2200/13
Inventor 王洁龚登凰杨敏孙文姣巨鹏瑶朱立峰王玉蒙张茜
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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